Stages of retinal tauopathy and its relation to age and non‐AD retinal pathologies

Abstract

AbstractBackgroundRetinal imaging for Alzheimer’s disease (AD) pathological features is a potential biomarker for AD. Amyloid β‐protein (Aβ) containing plaques and abnormally phosphorylated tau (p‐tau) pathology have been reported in retinas of AD cases. However, little is known about these pathologies in the retinas of patients without clinically known AD. Therefore, we analyzed retina samples from autopsy and biopsy cases from individuals without known AD for Aβ and tau pathology, to clarify the role of these lesions in non‐AD individuals with and without other eye disorders.MethodWe analyzed retina samples from 140 biopsy and 3 autopsy cases (age: 34 – 96 years; mean: 67 years). Paraffin‐embedded cross‐sections of the retina were stained with hematoxylin & eosin and with antibodies against Aβ and different p‐tau species. Additionally, we screened for the presence of fibrillar tau aggregates with the Gallyas silver method.ResultAβ plaques were not detected. We found a hierarchical sequence of the expansion of p‐tau pathology in the retina, which allowed to distinguish four stages of retinal tauopathy distribution: 0 = no retinal tauopathy (n = 36); 1 = pS202/pT205‐tau pathology restricted to the outer plexiform layer (OPL) (n = 41); 2 = pS202/pT205‐tau pathology restricted to OPL and inner nuclear layer (INL) (n = 23); stage 3 = pS202/pT205‐tau pathology in OPL, INL, and inner plexiform layer (n = 43). Antibodies against pS202/pT205‐tau, pT231‐tau, and MC1‐tau showed comparable results. Neurofibrillary tangles were not found. The distribution of the stages was not associated with age. However, all three non‐diseased controls did not exhibit retinal tauopathy whereas more than 70% of the cases with ocular tumors, inflammation, retina degeneration, and/or gliosis showed signs of a retinal tauopathy.ConclusionHere, we describe the presence of a retinal tauopathy in individuals over 33 years of age. It shows three stages in its evolution, which were in our sample not associated with age but with the occurrence of significant ophthalmopathological alterations. Whether these changes represent a primary retinal tauopathy or an initial stage of retinal AD pathology requires future studies.FundingStichting Alzheimer Onderzoek SAO‐FRA 2020‐017